The present invention relates to a new process for the preparation of pyrimidone derivatives with antifungal activity.
Patent application WO 97/05130 describes a series of pyrimidone derivatives with potent antifungal activity. Amongst the compounds described in this patent, those optically active compounds with a stereochemistry (R,R) are preferred. A particularly preferred compound is (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl]quinazolin-4(3H)-one, which is known in the literature as UR-9825.
The process described to date for the preparation of these optically active pyrimidone derivatives suffers from certain disadvantages when considered for industrial scale application. It is therefore necessary to find an alternative process to prepare these optically active pyrimidone derivatives, and specially UR-9825.
The present invention thus relates to a new process for the preparation of pyrimidone derivatives of general formula I, 
wherein:
Ar represents phenyl or phenyl substituted with one or more halogen and/or trifluoromethyl groups;
R1 is C1-C4 alkyl;
R2 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or cyclopropyl;
A represents a benzene ring or a 5- or 6-membered heterocyclic ring wherein one or more of the ring atoms are selected from the group consisting of N, O and S, which rings can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, and wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings;
a group W represents C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, xe2x80x94NR3R4, xe2x80x94CONR3R4, xe2x80x94CH2xe2x80x94OCOxe2x80x94R3, xe2x80x94COxe2x80x94R3, xe2x80x94COOxe2x80x94R3, xe2x80x94SOzR5, xe2x80x94C(xe2x95x90NR3)NHR6, xe2x80x94C(xe2x95x90NR6)OR3, and additionally one of the groups W can also represent 1-pyrrolyl, 1-imidazolyl, 1H-1,2,4-triazol-1-yl, 5-tetrazolyl (optionally substituted with C1-C4 alkyl), 1-pyrrolidinyl, 4-morpholinyl, 4-morpholinyl-N-oxide, a group xe2x80x94Xxe2x80x94R7, or a group of formula (i)-(iv): 
R3 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or arylC1-C4 alkyl, wherein aryl represents phenyl or phenyl substituted with one or more C1-C4 alkyl, halogen, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy groups;
R4 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94COR3 or xe2x80x94COCF3;
R5 represents C1-C4 alkyl;
z represents 0, 1 or 2;
R6 represents hydrogen, xe2x80x94CONH2, xe2x80x94COCH3, xe2x80x94CN, xe2x80x94SO2NHR3, xe2x80x94SO2R3, xe2x80x94OR3, xe2x80x94OCOR3 or xe2x80x94(C1-4 alkyl)xe2x80x94NH2;
X represents a single bond, xe2x80x94Oxe2x80x94, xe2x80x94SOzxe2x80x94, xe2x80x94NR3xe2x80x94, or xe2x80x94C(xe2x95x90O)xe2x80x94;
R7 represents a phenyl group optionally substituted with one or more groups R8;
R8 represents C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro, cyano, xe2x80x94NR3R4, xe2x80x94CONR3R4, xe2x80x94CH2xe2x80x94OCOxe2x80x94R3, xe2x80x94COxe2x80x94R3, xe2x80x94COOxe2x80x94R3, xe2x80x94SOzR5, xe2x80x94C(xe2x95x90NR3)NHR6, xe2x80x94C(xe2x95x90NR6)OR3, a group of formula (iv) or R8 represents a phenyl group (optionally substituted with a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, halogen, nitro or cyano group);
R9 represents hydrogen or methyl;
R10 represents hydrogen, isopropyl, cyclopentyl, cyclopropyl, 2-butyl, 3-pentyl, 3-hydroxy-2-butyl, or 2-hydroxy-3-pentyl;
m represents 0 or 1;
R11 represents halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, amino, cyano, or a group of formula (i);
Y represents xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94; and
Z represents NH or O;
which comprises reacting a compound of formula II 
wherein R1 and Ar have the meaning defined above in relation to formula I, with a compound of formula III 
wherein A and R2 have the meaning defined above in relation to formula I, in the presence of a base.
In the above definitions, the term C1-C4 alkyl, as a group or part of a group, means a straight or branched alkyl group having from 1 to 4 carbon atoms. Therefore, it includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
A C1-C4 haloalkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-C4 alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples thereof include trifluoromethyl, trichloromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, pentachloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-chloropropyl, 3,3-dichloropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentachloropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2, 3,3,3-pentafluoropropyl, heptafluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 4-iodobutyl and 4-bromobutyl.
A C3-C6 cycloalkyl group represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
A C1-C4 alkoxy group means a group derived from the union of a C1-C4 alkyl group to an oxygen atom of an ether functional group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
A C1-C4 haloalkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a C1-C4 alkoxy group with one or more halogen atoms, which can be the same or different. Examples include trifluoromethoxy, fluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, and 4-chlorobutoxy.
Halogen represents a fluoro, chloro, bromo or iodo atom.
An arylC1-C4 alkyl group means a group resulting from the substitution of a hydrogen atom of a C1-C4 alkyl group with an aryl group, wherein aryl is as defined above.
In a preferred embodiment, in the preparation process which is the object of the invention R2 represents hydrogen, methyl, trifluoromethyl or cyclopropyl; Ar represents 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and A represents a benzene ring, which can be optionally fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, or A represents a 5- or 6-membered heterocyclic ring wherein one or more of said ring atoms are selected from the group consisting of N, O and S and which can be optionally fused to a benzene ring, wherein A can be unsubstituted or have 1, 2, 3 or 4 substituents W in any of the rings.
In a more preferred embodiment, R1 represents methyl; R2 represents hydrogen; Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and A represents a benzene ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, wherein A can be unsubstituted or have 1, 2, 3 or 4 groups W.
In a still more preferred embodiment, R1 represents methyl; R2 represents hydrogen; Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; A represents a benzene ring optionally substituted with 1, 2, 3 or 4 groups W; and each W independently represents halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy or cyano.
In a particularly preferred embodiment, the process of the invention is used to prepare a compound of formula I which is (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4 (3H)-one (UR-9825) and it comprises reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane with 7-chloro-3H-quinazolin-4-one in the presence of a base.
The process for the preparation of the compounds of formula I which is the object of the invention can be summarized in the following scheme: 
The reaction between an epoxide of formula II and a compound of formula III is carried out in the presence of a base, such as for example sodium hydride, potassium carbonate, butyllithium, sodium hexamethyldisilazane (NaHMDS), lithium hexamethyldisilazane (LiHMDS) or potassium hexamethyldisilazane (KHMDS), in a suitable solvent, such as for example a polar solvent such as a substituted amide (e.g. N-methylpyrrolidone or dimethylformamide) or an ether (e.g. tetrahydrofuran or dioxane), at a temperature preferably comprised between room temperature and that of the boiling point of the solvent.
The product of formula I thus obtained can be isolated in a conventional manner and can be purified by standard methods well known to those skilled in the art, such as for example by recrystallization from a suitable solvent.
The starting epoxides of formula II are known compounds and can be prepared using any of the methods already described, for example by following the process described by Tasaka et al. in Chem. Pharm. Bull. 1993, 41(6), 1035-1042.
The compounds of formula III can be prepared from the compounds of formula IV by reaction with a reactive derivative of an acid R2CO2H, such as its alkyl imidate (for example the methyl or ethyl imidate), its amidine, its acid chloride, its anhydride or its trialkylorthoester, preferably its amidine or trialkylorthoester, at a temperature generally over 50xc2x0 C., as shown in the following scheme: 
In its turn, the compounds of formula IV are either commercially available or can be prepared by conventional processes, for example from an acid of formula V by treatment with ammonium hydroxide in the presence of a suitable coupling agent, for example dicyclohexylcarbodiimide, alone or associated with 1-hydroxybenzotriazole, in a polar solvent, such as a substituted amide (for example N-methylpyrrolidone or dimethylformamide) or an ether (for example tetrahydrofuran or dioxane), at a temperature preferably comprised between 0xc2x0 C. and 100xc2x0 C., or from the corresponding nitrile, for example a benzonitrile, by hydrolysis under the standard conditions widely known to those skilled in the art.
The acids of formula V and of formula R2COOH or derivatives thereof are commercially available, are widely described in the literature or can be prepared by methods analogous to those described in the literature, for example as described in Bartroli et al. J.Med.Chem. 1998, 41, 1855-1868.